The overall objective of this program is to investigate relationships between blood coagulation and the pathogenesis of diffuse intravascular clotting and of localized thrombosis. The program is divided into biochemical, physiological, immunological and clinical projcts. The biochemical projects include: (1) a search for mechanisms for activation of purified factor XI independent of plasma factor XII, (2) studies of the activation of purified factor IX, (3) studies of the mechanism of the increased reactivity of factor VII which results from contact activation and from steps in purification, and (4) separation and characterization of a cofactor of the lupus anticoagulan present in normal plasma. The physiological projects include: (1) studies of the mechanism for stimulation of fibrinogen synthesis by endotoxin, and (2) studies of the mechanism for stimulation of fibrinogen synthesis by products formed at local inflammatory sites. The immunological projects include: (1) studies of the mechanism of antigen-antibody induced intravascular clotting in cortisone-treated rabbits, (2) studies of intravascular clotting induced by endotoxin in rabbits made thrombocytopenic by anti-platelet antiserum absorbed to remove fibrinogen antibodies, (3) investigation of the effect of selective factor VII deficiency upon the ability of endotoxin to induce intravascular clotting in rabbits. The clinical projects include: (1) study of genetic mechanisms for hereditary factor XI deficiency utilizing an antibody against factor XI t look for antigenic material in the plasma of patients with hereditary factor XI deficiency, (2) standardization of test methods for monitoring heparin thrapy, and (3) studies of the effect of drugs altering platelet function in vitro upon the bleeding time of patients with severe hemophilia.